17-4899337-GGGC-GGGCGGC

Variant names:

• chr17-4899337-G-GGGC
• rs752226476
• NM_000080.4:c.1077_1079dupGCC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_000080.4(CHRNE):​c.1077_1079dupGCC​(p.Pro360dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00039 in 1,547,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P360P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: CHRNE NM_000080.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 0.170
• Publications: 0 publications found

Genes affected

CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

C17orf107 (HGNC:37238): (chromosome 17 open reading frame 107)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000080.4. Strenght limited to Supporting due to length of the change: 1aa.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000080.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	NM_000080.4	MANE Select	c.1077_1079dupGCC	p.Pro360dup	disruptive_inframe_insertion	Exon 10 of 12	NP_000071.1
	C17orf107	NM_001145536.2	MANE Select	c.-426_-425insGGC		upstream_gene	N/A	NP_001139008.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.1077_1079dupGCC	p.Pro360dup	disruptive_inframe_insertion	Exon 10 of 12	ENSP00000497829.1
	CHRNE	ENST00000649830.1		c.144_146dupGCC	p.Pro49dup	disruptive_inframe_insertion	Exon 10 of 11	ENSP00000496907.1
	CHRNE	ENST00000572438.1	TSL:5	n.763_765dupGCC		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes AF: 0.000527 AC: 80 AN: 151852 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000778

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000361 AC: 53 AN: 146728 AF XY: 0.000368

Gnomad AFR exome AF: 0.000270

Gnomad AMR exome AF: 0.000208

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.000355

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.000237

GnomAD4 exome AF: 0.000373 AC: 521 AN: 1395812 Hom.: 0 Cov.: 35 AF XY: 0.000392 AC XY: 271 AN XY: 690526

African (AFR) AF: 0.000189 AC: 6 AN: 31714

American (AMR) AF: 0.000168 AC: 6 AN: 35786

Ashkenazi Jewish (ASJ) AF: 0.00136 AC: 34 AN: 25046

East Asian (EAS) AF: 0.000275 AC: 10 AN: 36414

South Asian (SAS) AF: 0.000446 AC: 36 AN: 80672

European-Finnish (FIN) AF: 0.0000265 AC: 1 AN: 37788

Middle Eastern (MID) AF: 0.000394 AC: 2 AN: 5072

European-Non Finnish (NFE) AF: 0.000358 AC: 389 AN: 1085262

Other (OTH) AF: 0.000637 AC: 37 AN: 58058

GnomAD4 genome AF: 0.000540 AC: 82 AN: 151968 Hom.: 0 Cov.: 32 AF XY: 0.000619 AC XY: 46 AN XY: 74294

African (AFR) AF: 0.000217 AC: 9 AN: 41468

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000780 AC: 4 AN: 5130

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 67908

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000699

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Jan 23, 2025

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 23, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame insertion of 1 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge

Nov 13, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myasthenic syndrome Uncertain:2

Jan 17, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 14, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Congenital myasthenic syndrome 4A Uncertain:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1077_1079dup, results in the insertion of 1 amino acid(s) of the CHRNE protein (p.Pro360dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs752226476, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CHRNE-related conditions. ClinVar contains an entry for this variant (Variation ID: 465852). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Congenital myasthenic syndrome 4C;C4225369:Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A Uncertain:1

Jul 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.17
Mutation Taster		=81/19	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752226476; hg19: chr17-4802632;